COG4

Summary

COG4 (component of oligomeric golgi complex 4, HGNC:18620) is a protein-coding gene on chromosome 16q22.1, encoding Conserved oligomeric Golgi complex subunit 4 (Q9H9E3). Required for normal Golgi function. It is a selective cancer dependency (DepMap: 42.7% of cell lines).

The protein encoded by this gene is a component of an oligomeric protein complex involved in the structure and function of the Golgi apparatus. Defects in this gene may be a cause of congenital disorder of glycosylation type IIj. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 25839 — RefSeq curated summary.

At a glance

• Gene–disease (curated): microcephalic osteodysplastic dysplasia, Saul-Wilson type (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 7
• Clinical variants (ClinVar): 482 total — 16 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 91
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 42.7% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_015386

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18620
Approved symbol	COG4
Name	component of oligomeric golgi complex 4
Location	16q22.1
Locus type	gene with protein product
Status	Approved
Aliases	COD1, DKFZP586E1519
Ensembl gene	ENSG00000103051
Ensembl biotype	protein_coding
OMIM	606976
Entrez	25839

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 12 protein_coding, 12 nonsense_mediated_decay, 7 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000323786, ENST00000393612, ENST00000482252, ENST00000524584, ENST00000526700, ENST00000530160, ENST00000530314, ENST00000534772, ENST00000562200, ENST00000564315, ENST00000564415, ENST00000564653, ENST00000565715, ENST00000567244, ENST00000674443, ENST00000703106, ENST00000703107, ENST00000703108, ENST00000703109, ENST00000703110, ENST00000703111, ENST00000703112, ENST00000703113, ENST00000703114, ENST00000703115, ENST00000876430, ENST00000876431, ENST00000876432, ENST00000912896, ENST00000912897, ENST00000959444, ENST00000959445

RefSeq mRNA: 3 — MANE Select: NM_015386 NM_001195139, NM_001365426, NM_015386

CCDS: CCDS10892, CCDS73909

Canonical transcript exons

ENST00000323786 — 19 exons

Exon	Start	End
ENSE00001284953	70523373	70523554
ENSE00001919638	70480571	70481144
ENSE00003463117	70514335	70514509
ENSE00003471752	70482729	70482821
ENSE00003486378	70482092	70482175
ENSE00003515733	70497937	70498055
ENSE00003517607	70509231	70509388
ENSE00003535648	70496266	70496431
ENSE00003538669	70517626	70517740
ENSE00003539514	70509916	70510021
ENSE00003544728	70500958	70501091
ENSE00003571692	70519649	70519731
ENSE00003578090	70497221	70497387
ENSE00003588968	70512239	70512432
ENSE00003609637	70481359	70481487
ENSE00003624648	70508406	70508464
ENSE00003627591	70481764	70481865
ENSE00003681706	70490330	70490392
ENSE00003691285	70483853	70483969

Expression profiles

Bgee: expression breadth ubiquitous, 273 present calls, max score 94.54.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.0462 / max 132.9588, expressed in 1807 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
157944	15.0462	1807

Top tissues by expression

290 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	94.54	gold quality
mucosa of transverse colon	UBERON:0004991	94.27	gold quality
apex of heart	UBERON:0002098	94.24	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.93	gold quality
right testis	UBERON:0004534	93.67	gold quality
granulocyte	CL:0000094	93.58	gold quality
gastrocnemius	UBERON:0001388	93.37	gold quality
muscle of leg	UBERON:0001383	93.28	gold quality
rectum	UBERON:0001052	93.26	gold quality
left testis	UBERON:0004533	93.13	gold quality
ventricular zone	UBERON:0003053	93.01	gold quality
endometrium epithelium	UBERON:0004811	92.60	silver quality
right adrenal gland	UBERON:0001233	92.45	gold quality
esophagus mucosa	UBERON:0002469	92.40	gold quality
right adrenal gland cortex	UBERON:0035827	92.39	gold quality
ganglionic eminence	UBERON:0004023	92.38	gold quality
metanephros cortex	UBERON:0010533	92.13	gold quality
islet of Langerhans	UBERON:0000006	92.06	gold quality
left adrenal gland	UBERON:0001234	91.88	gold quality
gall bladder	UBERON:0002110	91.82	gold quality
left adrenal gland cortex	UBERON:0035825	91.82	gold quality
muscle organ	UBERON:0001630	91.51	gold quality
stromal cell of endometrium	CL:0002255	91.39	gold quality
right lobe of liver	UBERON:0001114	91.33	gold quality
right lobe of thyroid gland	UBERON:0001119	91.25	gold quality
testis	UBERON:0000473	91.22	gold quality
spleen	UBERON:0002106	91.06	gold quality
adenohypophysis	UBERON:0002196	91.06	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.05	gold quality
adrenal cortex	UBERON:0001235	91.03	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.11

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

11 targeting COG4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-142-3P	99.62	71.30	974
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4721	99.26	66.05	818
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-6882-3P	98.23	67.01	1119
HSA-MIR-6765-3P	97.83	64.59	1165
HSA-MIR-6736-3P	96.98	65.22	1342
HSA-MIR-3616-3P	96.96	65.45	983
HSA-MIR-3194-5P	96.80	64.90	1027
HSA-MIR-12128	96.67	66.98	1471
HSA-MIR-1226-5P	96.50	65.28	643

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 42.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 6)

• A novel R729W missense mutation in COG4 was associated with the congenital disorder of glycosylation type II. (PMID:19494034)
• Study shows that the SM protein, Sly1, interacts directly with the conserved oligomeric Golgi (COG) tethering complex; Sly1-COG interaction is mediated by the Cog4 subunit, which also interacts with Syntaxin 5 through a different binding site. (PMID:19536132)
• The 1.9 A crystal structure of a Cog4 C-terminal fragment, was determined. Arg 729 is found to occupy a key position at the center of a salt bridge network, thereby stabilizing Cog4’s small C-terminal domain. (PMID:19651599)
• TMEM-COG4, COG7 and COG8 subunits restore endogenous COG localization to the Golgi membranes (PMID:29467253)
• A specific heterozygous COG4 substitution as the molecular basis of Saul-Wilson syndrome. (PMID:30290151)
• Growth in individuals with Saul-Wilson syndrome. (PMID:32652690)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cog4	ENSDARG00000054264
mus_musculus	Cog4	ENSMUSG00000031753
rattus_norvegicus	Cog4	ENSRNOG00000017745
drosophila_melanogaster	Cog4	FBGN0032258
caenorhabditis_elegans		WBGENE00021784

Paralogs (1): DNAJC28 (ENSG00000177692)

Protein

Protein identifiers

Conserved oligomeric Golgi complex subunit 4 — Q9H9E3 (reviewed: Q9H9E3)

Alternative names: Component of oligomeric Golgi complex 4

All UniProt accessions (16): Q9H9E3, A0A0A0MS45, A0A6I8PIQ6, A0A8V8TQ33, A0A8V8TQ38, A0A8V8TQL5, A0A8V8TQL9, A0A8V8TQM1, A0A8V8TR60, A0A8V8TRG1, E9PRT5, H3BQB2, H3BSD2, J3KNI1, J3KRB5, J3QLW1

UniProt curated annotations — full annotation on UniProt →

Function. Required for normal Golgi function. Plays a role in SNARE-pin assembly and Golgi-to-ER retrograde transport via its interaction with SCFD1.

Subunit / interactions. Monomer. Component of the conserved oligomeric Golgi (COG) complex which is composed of eight different subunits and is required for normal Golgi morphology and localization. Mediates interaction of SCFD1 with the COG complex. Interacts with STX5.

Subcellular location. Cytoplasm. Cytosol. Golgi apparatus membrane.

Disease relevance. Congenital disorder of glycosylation 2J (CDG2J) [MIM:613489] A multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. The disease is caused by variants affecting the gene represented in this entry. Saul-Wilson syndrome (SWILS) [MIM:618150] A rare skeletal dysplasia with characteristic dysmorphic and radiographic findings, as well as early developmental delay, primarily involving speech, with eventual normal cognition. Clinical findings include marked short stature, prominent forehead with an enlarged anterior fontanel, prominent eyes with cataracts, narrow nasal bridge with a convex nasal ridge, micrognathia, clubfoot, brachydactyly, and short distal phalanges of fingers. Radiographic changes include platyspondyly, irregular end plates of vertebral bodies, and hypoplasia of the odontoid process with cervical instability in the spine, coxa valga, overtubulation, metaphyseal flaring and megaepiphyses in the long bones, while the hands and feet exhibit short phalanges, metacarpals and metatarsals, cone-shaped epiphyses of phalanges, and accessory ossification centers of metacarpals and metatarsals. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the COG4 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9H9E3-1	1	yes
Q9H9E3-2	2, Cog4S
Q9H9E3-3	3

RefSeq proteins (3): NP_001182068, NP_001352355, NP_056201* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013167	COG4_M	Domain
IPR048680	COG4_N	Domain
IPR048682	COG4	Family
IPR048684	COG4_C	Domain

Pfam: PF08318, PF20662, PF20663

UniProt features (38 total): helix 14, sequence conflict 6, region of interest 5, splice variant 3, sequence variant 3, mutagenesis site 2, modified residue 2, initiator methionine 1, chain 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3HR0	X-RAY DIFFRACTION	1.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H9E3-F1	85.29	0.50

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 2, 6

Mutagenesis-validated functional residues (2):

Position	Phenotype
729	severe defects in glycosylation.
764	severe defects in glycosylation.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6807878	COPI-mediated anterograde transport
R-HSA-6811438	Intra-Golgi traffic
R-HSA-6811440	Retrograde transport at the Trans-Golgi-Network

MSigDB gene sets: 307 (showing top): chr16q22, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GOBP_INTRA_GOLGI_VESICLE_MEDIATED_TRANSPORT, MODULE_205, GOCC_TRANS_GOLGI_NETWORK, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, GOBP_GOLGI_ORGANIZATION, GOCC_GOLGI_TRANSPORT_COMPLEX, GOCC_TRANS_GOLGI_NETWORK_MEMBRANE, SCGGAAGY_ELK1_02, GOCC_ORGANELLE_SUBCOMPARTMENT, MORF_PRKAR1A, GOBP_GOLGI_VESICLE_TRANSPORT

GO Biological Process (5): retrograde transport, vesicle recycling within Golgi (GO:0000301), retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum (GO:0006890), Golgi organization (GO:0007030), protein transport (GO:0015031), obsolete glycosylation (GO:0070085)

GO Molecular Function (2): identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (7): Golgi membrane (GO:0000139), cytosol (GO:0005829), COG complex (GO:0017119), trans-Golgi network membrane (GO:0032588), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Intra-Golgi and retrograde Golgi-to-ER traffic	2
ER to Golgi Anterograde Transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
Golgi apparatus	2
cytoplasm	2
intra-Golgi vesicle-mediated transport	1
Golgi vesicle transport	1
organelle organization	1
endomembrane system organization	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
protein binding	1
binding	1
bounding membrane of organelle	1
vesicle tethering complex	1
trans-Golgi network	1
organelle membrane	1
intracellular anatomical structure	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1100 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COG4	COG2	Q14746	995
COG4	COG3	Q96JB2	994
COG4	COG1	Q8WTW3	994
COG4	COG7	P83436	984
COG4	COG8	Q96MW5	980
COG4	COG5	Q9UP83	978
COG4	COG6	Q9Y2V7	961
COG4	STX5	Q13190	940
COG4	SCFD1	Q8WVM8	930
COG4	VPS53	Q5VIR6	826
COG4	ZNF787	Q6DD87	725
COG4	EXOC3	O60645	717
COG4	STX16	O14662	711
COG4	VPS54	Q9P1Q0	709
COG4	PMM2	O15305	694

IntAct

174 interactions, top by confidence:

A	B	Type	Score
NUP54	NUP58	psi-mi:“MI:0914”(association)	0.950
PIK3CA	PIK3R2	psi-mi:“MI:0914”(association)	0.900
PSMC5	PSMD11	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
COG2	COG4	psi-mi:“MI:0915”(physical association)	0.670
COG4	COG2	psi-mi:“MI:0915”(physical association)	0.670
COG7	COG4	psi-mi:“MI:0915”(physical association)	0.670
COG4	COG7	psi-mi:“MI:0915”(physical association)	0.670
COG4	COG7	psi-mi:“MI:0914”(association)	0.670
SCFD1	COG4	psi-mi:“MI:0915”(physical association)	0.670
SCFD1	COG4	psi-mi:“MI:0407”(direct interaction)	0.670
COG4	SCFD1	psi-mi:“MI:0915”(physical association)	0.670
COMMD8	VPS26C	psi-mi:“MI:0914”(association)	0.640
VSIG1	TTI1	psi-mi:“MI:0914”(association)	0.640
COG3	COG7	psi-mi:“MI:0914”(association)	0.640
COG7	ILVBL	psi-mi:“MI:0914”(association)	0.640
SCN2B	EXOC5	psi-mi:“MI:0914”(association)	0.640
GYPA	TCAF2	psi-mi:“MI:0914”(association)	0.640
SORBS3	COG4	psi-mi:“MI:0915”(physical association)	0.560
COG4	FARSA	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (178): COG4 (Affinity Capture-MS), COG4 (Affinity Capture-MS), COG4 (Affinity Capture-MS), COG4 (Affinity Capture-MS), COG4 (Affinity Capture-MS), COG4 (Affinity Capture-MS), COG4 (Affinity Capture-MS), COG1 (Co-fractionation), COG4 (Co-fractionation), COG4 (Co-fractionation), COG4 (Co-fractionation), COG4 (Co-fractionation), COG6 (Co-fractionation), COG7 (Co-fractionation), COG4 (Affinity Capture-MS)

ESM2 similar proteins: A1A4I4, A2SXS5, A6QQ47, B2DCZ9, O00255, O08908, O55166, O75146, O88559, P70268, Q0P5I0, Q0VCR8, Q155U0, Q16512, Q29RB1, Q2KJ58, Q3MHG0, Q3MII6, Q3SZI7, Q3UVL4, Q4V9Y0, Q505L3, Q5R7R6, Q5TJF0, Q5ZJ25, Q63433, Q63788, Q68FF6, Q68FP9, Q69Z89, Q6PB44, Q6ZT62, Q865S3, Q8BI71, Q8BZQ7, Q8C190, Q8C754, Q8N1B4, Q8R1U1, Q8R3I3

Diamond homologs: Q29RB1, Q3MHG0, Q5R7R6, Q8L838, Q8R1U1, Q95TN4, Q95XZ0, Q9H9E3

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
COG4	“form complex”	“COG tethering complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 146 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Intra-Golgi traffic	9	25.9×	3e-08
Retrograde transport at the Trans-Golgi-Network	7	17.1×	3e-05
GSK3B-mediated proteasomal degradation of PD-L1(CD274)	5	13.2×	5e-03
SPOP-mediated proteasomal degradation of PD-L1(CD274)	5	12.7×	5e-03
Defective CFTR causes cystic fibrosis	5	12.2×	5e-03
COPI-mediated anterograde transport	9	11.0×	3e-05
Regulation of RAS by GAPs	5	10.8×	7e-03
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	5	10.8×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
intra-Golgi vesicle-mediated transport	6	25.3×	5e-05
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	5	13.5×	5e-03
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	6	10.5×	5e-03
Golgi organization	9	9.6×	1e-04
protein transport	12	4.2×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

482 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	13
Uncertain significance	258
Likely benign	103
Benign	49

Top pathogenic / likely-pathogenic (29)

Variant ID	HGVS	Classification
1172782	NM_015386.3(COG4):c.1255G>T (p.Glu419Ter)	Pathogenic
1454863	NM_015386.3(COG4):c.883G>T (p.Glu295Ter)	Pathogenic
2446151	NM_015386.3(COG4):c.844+1G>A	Pathogenic
2917150	NM_015386.3(COG4):c.1608del (p.Gly537fs)	Pathogenic
31927	NM_015386.3(COG4):c.697G>T (p.Glu233Ter)	Pathogenic
31928	NM_015386.3(COG4):c.2318T>G (p.Leu773Arg)	Pathogenic
449595	NM_015386.3(COG4):c.844+2T>A	Pathogenic
449730	NM_015386.3(COG4):c.1546G>A (p.Gly516Arg)	Pathogenic
4689131	NM_015386.3(COG4):c.1828delG	Pathogenic
4719224	NM_015386.3(COG4):c.1434_1435del (p.Ala480fs)	Pathogenic
4726045	NM_015386.3(COG4):c.1122dup (p.Arg375fs)	Pathogenic
4812006	NM_015386.3(COG4):c.1955G>A (p.Trp652Ter)	Pathogenic
571433	NM_015386.3(COG4):c.6del (p.Thr3fs)	Pathogenic
585271	NM_015386.3(COG4):c.1546G>C (p.Gly516Arg)	Pathogenic
599648	NM_015386.3(COG4):c.1840G>T (p.Glu614Ter)	Pathogenic
862921	NM_015386.3(COG4):c.599_600del (p.Lys200fs)	Pathogenic
1172781	NM_015386.3(COG4):c.941G>A (p.Cys314Tyr)	Likely pathogenic
1518423	NM_015386.3(COG4):c.544+1G>T	Likely pathogenic
3065305	NM_015386.3(COG4):c.1002+1G>T	Likely pathogenic
3065319	NM_015386.3(COG4):c.2006C>T (p.Ala669Val)	Likely pathogenic
3340758	NM_015386.3(COG4):c.15G>A (p.Met5Ile)	Likely pathogenic
3377650	NM_015386.3(COG4):c.433G>T (p.Gly145Ter)	Likely pathogenic
3581232	NM_015386.3(COG4):c.1290C>A (p.Tyr430Ter)	Likely pathogenic
419327	NM_015386.3(COG4):c.1809del (p.Lys603fs)	Likely pathogenic
4714046	NM_015386.3(COG4):c.739-1G>C	Likely pathogenic
4849452	NM_015386.3(COG4):c.289C>T (p.Gln97Ter)	Likely pathogenic
545073	NM_015386.3(COG4):c.2005G>C (p.Ala669Pro)	Likely pathogenic
971970	NM_015386.3(COG4):c.369+1_369+2del	Likely pathogenic
988419	NM_015386.3(COG4):c.1558G>A (p.Ala520Thr)	Likely pathogenic

SpliceAI

3026 predictions. Top by Δscore:

Variant	Effect	Δscore
16:70481140:GTCAC:G	acceptor_gain	1.0000
16:70481141:TCAC:T	acceptor_gain	1.0000
16:70481142:CAC:C	acceptor_gain	1.0000
16:70481142:CACC:C	acceptor_gain	1.0000
16:70481143:AC:A	acceptor_gain	1.0000
16:70481144:CCTG:C	acceptor_gain	1.0000
16:70481145:C:CC	acceptor_gain	1.0000
16:70481147:G:C	acceptor_gain	1.0000
16:70481147:G:GC	acceptor_gain	1.0000
16:70481355:CTAC:C	donor_loss	1.0000
16:70481356:TACC:T	donor_loss	1.0000
16:70481357:A:AC	donor_gain	1.0000
16:70481358:C:CC	donor_gain	1.0000
16:70481358:CCCG:C	donor_gain	1.0000
16:70481431:C:CT	acceptor_gain	1.0000
16:70481483:CCCAG:C	acceptor_gain	1.0000
16:70481484:CCAG:C	acceptor_gain	1.0000
16:70481484:CCAGC:C	acceptor_gain	1.0000
16:70481485:CAG:C	acceptor_gain	1.0000
16:70481485:CAGC:C	acceptor_gain	1.0000
16:70481486:AG:A	acceptor_gain	1.0000
16:70481488:C:CC	acceptor_gain	1.0000
16:70481488:CT:C	acceptor_loss	1.0000
16:70481759:CTTA:C	donor_loss	1.0000
16:70481760:TTA:T	donor_loss	1.0000
16:70481762:A:AC	donor_gain	1.0000
16:70481762:AC:A	donor_gain	1.0000
16:70481763:C:CC	donor_gain	1.0000
16:70481763:CC:C	donor_gain	1.0000
16:70481861:CTGGC:C	acceptor_gain	1.0000

AlphaMissense

5228 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000153168 (16:70500350 T>C), RS1000163720 (16:70506333 G>T), RS1000210524 (16:70515599 G>A), RS1000309414 (16:70521434 T>C), RS1000370670 (16:70511402 G>A), RS1000420352 (16:70500519 C>T), RS1000473866 (16:70488388 A>C,G), RS1000550737 (16:70484869 C>T), RS1000581957 (16:70515841 A>G), RS1000604663 (16:70494305 T>G), RS1000694779 (16:70484653 C>T), RS1000720813 (16:70483549 G>A,C), RS1000740450 (16:70511167 CTG>C), RS1000762214 (16:70500111 C>A,T), RS1000784345 (16:70521251 C>T)

Disease associations

OMIM: gene MIM:606976 | disease phenotypes: MIM:613489, MIM:618150

GenCC curated gene-disease

Disease	Classification	Inheritance
COG4-congenital disorder of glycosylation	Definitive	Autosomal recessive
microcephalic osteodysplastic dysplasia, Saul-Wilson type	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
microcephalic osteodysplastic dysplasia, Saul-Wilson type	Definitive	AD
COG4-congenital disorder of glycosylation	Moderate	AR

Mondo (2): COG4-congenital disorder of glycosylation (MONDO:0013281), microcephalic osteodysplastic dysplasia, Saul-Wilson type (MONDO:0019407)

Orphanet (2): COG4-CDG (Orphanet:263501), Microcephalic osteodysplastic dysplasia, Saul-Wilson type (Orphanet:85172)

HPO phenotypes

91 total (30 of 91 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000260	Wide anterior fontanel
HP:0000272	Malar flattening
HP:0000340	Sloping forehead
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000444	Convex nasal ridge
HP:0000446	Narrow nasal bridge
HP:0000518	Cataract
HP:0000520	Proptosis
HP:0000592	Blue sclerae
HP:0000639	Nystagmus
HP:0000662	Nyctalopia
HP:0000737	Irritability
HP:0000750	Delayed speech and language development
HP:0000767	Pectus excavatum
HP:0000768	Pectus carinatum
HP:0000926	Platyspondyly
HP:0001015	Prominent superficial veins
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001394	Cirrhosis
HP:0001399	Hepatic failure

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST002541_109	Menarche (age at onset)	6.000000e-21
GCST002541_110	Menarche (age at onset)	1.000000e-11
GCST006993_12	Hippocampal volume in Alzheimer’s disease dementia	1.000000e-07
GCST008152_96	Weight	3.000000e-06
GCST010703_100	Brain morphology (MOSTest)	2.000000e-40
GCST010725_47	Malaria	6.000000e-07
GCST90013406_213	Liver enzyme levels (alkaline phosphatase)	2.000000e-10

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0005035	hippocampal volume
EFO:0004338	body weight
EFO:0004346	neuroimaging measurement
EFO:0004533	alkaline phosphatase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105733 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.66	Kd	22	nM	CHEMBL5653589
7.65	ED50	22.17	nM	CHEMBL5653589
5.34	Kd	4576	nM	CHEMBL3752910
5.34	ED50	4612	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 6 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148106: Binding affinity to human COG4 incubated for 45 mins by Kinobead based pull down assay	kd	0.0220	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148106: Binding affinity to human COG4 incubated for 45 mins by Kinobead based pull down assay	kd	4.5759	uM

CTD chemical–gene interactions

44 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
methacrylaldehyde	affects cotreatment, decreases expression, increases oxidation, increases abundance	2
Acetaminophen	decreases expression, increases expression	2
Acrolein	increases abundance, affects cotreatment, decreases expression, increases oxidation	2
Air Pollutants	decreases expression, increases abundance, increases expression, affects cotreatment	2
Ozone	increases oxidation, increases abundance, affects cotreatment, decreases expression	2
Rotenone	decreases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
bisphenol A	affects expression	1
beta-lapachone	decreases expression, increases expression	1
sodium arsenite	decreases expression, increases abundance, affects cotreatment	1
cobaltous chloride	decreases expression	1
manganese chloride	increases abundance, affects cotreatment, decreases expression	1
aflatoxin B2	decreases methylation	1
di-n-butylphosphoric acid	affects expression	1
acyline	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Cadmium	increases abundance, increases expression	1
Caffeine	increases phosphorylation	1
Coumestrol	increases expression	1
Dimethyl Sulfoxide	increases expression	1
Dinitrochlorobenzene	affects binding	1
Doxorubicin	increases expression	1
Ivermectin	decreases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Nickel	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4012603	Binding	Binding affinity to COG4 in human INA-6 cells after 3 hrs by nanoLC-MS/MS method	Ugi Reaction-Derived α-Acyl Aminocarboxamides Bind to Phosphatidylinositol 3-Kinase-Related Kinases, Inhibit HSF1-Dependent Heat Shock Response, and Induce Apoptosis in Multiple Myeloma Cells. — J Med Chem

Clinical trials (associated diseases)

1 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04569149	Not specified	RECRUITING	Primordial Dwarfism Registry